Epidermal Growth Factor Receptor as Target for Perioperative Elimination of Circulating Colorectal Cancer Cells.

Mandy Gruijs,Marije B Overdijk,Berend J Van Der Wilk,Tessa Hellingman,Marjolein Van Egmond,Paul W H I Parren,Marijn Bögels,Rens Braster,Sandra Verploegen,Hans J Van Der Vliet,Rianne Korthouwer,Yingming Sun

doi:10.1155/2022/3577928

Abstract

Surgical resection of the tumor is the primary treatment of colorectal cancer patients. However, we previously demonstrated that abdominal surgery promotes the adherence of circulating tumor cells (CTC) in the liver and subsequent liver metastasis development. Importantly, preoperative treatment with specific tumor-targeting monoclonal antibodies (mAb) prevented surgery-induced liver metastasis development in rats. This study investigated whether the epidermal growth factor receptor (EGFR) represents a suitable target for preoperative antibody treatment of colorectal cancer patients undergoing surgery. The majority of patients with resectable colorectal liver metastases were shown to have EGFR + CTCs. Three different anti-EGFR mAbs (cetuximab, zalutumumab, and panitumumab) were equally efficient in the opsonization of tumor cell lines. Additionally, all three mAbs induced antibody-dependent cellular phagocytosis (ADCP) of tumor cells by macrophages at low antibody concentrations in vitro, independent of mutations in EGFR signaling pathways. The plasma of cetuximab-treated patients efficiently opsonized tumor cells ex vivo and induced phagocytosis. Furthermore, neither proliferation nor migration of epithelial cells was affected in vitro, supporting that wound healing will not be hampered by treatment with low anti-EGFR mAb concentrations. These data support the use of a low dose of anti-EGFR mAbs prior to resection of the tumor to eliminate CTCs without interfering with the healing of the anastomosis. Ultimately, this may reduce the risk of metastasis development, consequently improving long-term patient outcome significantly.

Highlights

Colorectal cancer is one of the most frequent types of cancer worldwide
We confirmed that tumor cells that had been preincubated with cetuximab showed similar binding to the anti-epidermal growth factor receptor (EGFR) detection antibody (Supplementary Figure 1(b)), indicating that both antiEGFR antibodies bind to different epitopes and do not interfere with each other
We previously demonstrated that antibody treatment could prevent surgeryinduced metastasis development, which was mediated through antibody-dependent cellular phagocytosis (ADCP) in a rat model. erefore, we investigated whether the available anti-EGFR monoclonal antibodies (mAb) induced ADCP of tumor cells by macrophages

Summary

Introduction

Approximately 1.9 million patients are diagnosed with colorectal cancer globally, and more than 935,000 patients die of this disease [1]. The development of liver metastases is frequently observed and associated with high morbidity and mortality [5]. E prognosis of patients with colorectal liver metastases is poor, with a median survival time of eight months without treatment, and 5-year survival rates of 15–50%, mainly depending on the presence of extrahepatic. Up to 75% of colorectal cancer patients have disseminated circulating tumor cells (CTC) in their blood [8, 9]. E presence of CTCs is correlated with poor survival of both patients with primary colorectal cancer and patients with resectable liver metastases [8, 11,12,13]. High postoperative levels of CTCs predicted tumor recurrence [11, 12]

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Conclusion